MicroRNAs, The Immune System and Rheumatic Disease

Esmerina Tili; Jean-Jacques Michaille; Stefan Costinean; Carlo M. Croce

Disclosures

Nat Clin Pract Rheumatol. 2008;4(10):534-541. 

In This Article

miRNA Processing and Function

Most miRNAs are generated, by RNA polymerase II, as long primary transcripts (pri-miRNAs) that form a stem-loop structure. Pri-miRNAs are capped, polyadenylated, and are usually spliced. In the nucleus, pri-miRNAs are processed into 70-100 nucleotide-long hairpin pre-miRNAs by the RNAse III Drosha and its cofactors DGRC8 (DiGeorge syndrome critical region gene 8) and RNA helicase (Figure 1). These pre-miRNAs are then exported into the cytoplasm in a complex with exportin-5 and RAS-like nuclear protein (Ran)-GTP.[20] They are then further processed by another RNAse III, Dicer, and its cofactor TRBP (trans-activation-response RNA-binding protein). The resultant approximately 22-nucleotide RNA duplexes contain the mature miRNA and the passenger miRNA strand.[20] The mature miRNA is loaded into the RISC (RNA-induced silencing complex), where it associates with one of the highly conserved Argonaute proteins. The miRNA-Argonaute complex interacts with the 3'-untranslated region (3'-UTR) of target messenger RNAs (mRNAs) through complementary binding of the miRNA to the mRNA. This binding either blocks translation initiation, induces the endonucleolytic cleavage of the target mRNA, or both.[20]

Figure 1.

MicroRNA biogenesis. Pri-miRNA transcripts are processed into pre-miRNAs by an enzymatic complex that includes the nuclear RNAse III enzyme Drosha and DGRC8. The resulting pre-miRNA is transported to the cytoplasm by exportin-5 and a Ran GTPase. Once in the cytoplasm, pre-miRNAs are processed into ~22-nucleotide duplexes by another RNAse III enzyme, Dicer, in association with TRBP. The strand corresponding to the mature miRNA is subsequently loaded onto the RISC. Mature miRNAs bind the 3'-untranslated region of target mRNAs and subsequently destabilize them, block their translation, or both. Abbreviations: DGRC8, DiGeorge syndrome critical region 8; mRNA, messenger RNA; miRNA, microRNA; pre-miRNA, precursor miRNA; pri-miRNA, primary miRNA; Ran, RAS-like nuclear protein; RISC, RNA-induced silencing complex; TRBP, trans-activation-response RNA-binding protein.

The mechanisms of miRNA action described above reflect the widely accepted notion that miRNAs act as post-transcriptional silencers. In some circumstances, however, miRNAs might enhance translation as well. For example, in resting macrophages, the 3'-UTR of TNF mRNA has been implicated in the repression of its own translation. Upon lipopolysaccharide (LPS) stimulation, these inhibitory effects are released, leading to TNF production and secretion.[21] Indeed, the coexpression of miR-155 (itself upregulated in response to LPS) with a construct containing the 3'-UTR of TNF fused downstream of a green fluorescent protein coding sequence leads to increased green fluorescence compared with controls expressing only the 3'-UTR of TNF fused with the green fluorescent protein coding sequence.[14] Similarly, the coexpression of miR-369-3 and a plasmid reporter for TNF 3'-UTR in serum-starved cells enhances TNF translation.[22] It is, however, too early to draw any conclusions regarding the molecular mechanisms for, or cellular settings that might favor, the enhancement of miRNA-mediated translation over repression for a given miRNA, or the elements responsible for this switch in function. Some miRNAs have also been hypothesized to induce the expression of genes whose promoters contain their target site, although further study is required to confirm this theory.[23]

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